Localization of Nonsyndromic Hearing Impairment Genes Non-syndromic hearing impairment (NSHI) is the most heterogeneous trait known, with > 140 mapped loci and >50 identified genes. However, the vast majority of NSHI genes have neither been localized nor identified. The extreme genetic heterogeneity of NSHI is due to the different processes which can malfunction within the inner ear and cause the hearing impairment (HI) phenotype. Identification of genes involved in HI is the first step in improving knowledge of the auditory process which in turn will aid in the development of diagnostic modalities and therapeutic interventions, and additionally aid in early diagnosis through genetic screening. In order to map and refine the interval for novel NSHI loci and NSHI loci with unknown genes, pedigrees segregating NSHI are being ascertained from throughout Pakistan. These pedigrees are usually both consanguineous and can independently establish linkage. Due to extreme locus heterogeneity of NSHI it is important that loci be mapped using families which can individually establish linkage. Consanguineous pedigrees are ideal for mapping autosomal recessive (AR) NSHI since homozygosity mapping can be performed, and unlike pedigrees without consanguineous matings, they can be sufficiently informative to establish linkage. Using DNA samples from the ascertained pedigrees, whole genome genotyping will be carried out using the Illumina Infinium HumanLinkage-12 panel. Linkage and haplotype analysis, and for consanguineous ARNSHI families homozygosity mapping, will be used to localize NSHI loci to the smallest possible genetic intervals. Information from multiple families with established linkage to the same genetic region will be used to refine the interval whenever possible. The study will provide a rich resource of families to carry out NSHI gene identification using next generation sequencing. Goal: To map NSHI loci and refine them to the smallest possible region using a large resource of well characterized families with NSHI. PUBLIC HEALTH RELEVANCE: Large consanguineous families with nonsyndromic hearing impairment (NSHI) will be ascertained from Pakistan. In order to map NSHI loci, linkage analysis will be carried using genotype data generated from SNP arrays. Completion of the aims of this proposal will provide a resource to identify genes for novel loci as well as for known NSHI loci for which the gene is unknown.